Tbx3 directs cell fate decision towards mesendoderm, pancreas and liver in mouse embryonic stem cells

Pluripotency depends on networks of key transcriptional regulators. Recent reports demonstrate additional functions of pluripotency-associated factors during early lineage commitment. The T-box transcription factor Tbx3 has been implicated in the regulation of embryonic stem cell (ESC) self-renewal and pluripotency. In this study, we demonstrate previously unappreciated roles of Tbx3 for the specification of mesendoderm. Tbx3 is dynamically expressed in murine embryos and in differentiating ESCs, concomitant with specification-onset of the mesendoderm lineages. Transcriptional profiling of differentiating ESCs during forced Tbx3 expression indicates enhanced mesendoderm specification and enrichment of mature endoderm derivatives namely pancreas and liver in prolonged differentiation cultures. Tbx3 directly activates key factors of lineage specification as assessed by ChIP and reporter assays and additionally promotes mesendoderm fate in a cell non-autonomous fashion by enhancing Nodal signaling. In summary, our data suggest cell autonomous and cell non-autonomous functions of Tbx3 for early lineage specification towards mesendoderm, thus, establishing a new path towards in vitro engineering of pancreas and liver for regenerative medicine.